Anisole → HCID 66605478, compound

HRID 2410796Notes

Reaction equation

HRID 2410796 reaction equation
C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[C:39]3[N:56]=[C:55]([C:57]4[CH:58]=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=4)[CH:54]=[C:53]([C:64]([O:66][CH3:67])=[O:65])[C:40]=3[N:41](CC3C=CC(OC)=CC=3)[C:42]=2[CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(OC)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:35]2[CH:36]=[CH:37][C:38]3[C:39]4[N:56]=[C:55]([C:57]5[CH:58]=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=5)[CH:54]=[C:53]([C:64]([O:66][CH3:67])=[O:65])[C:40]=4[NH:41][C:42]=3[CH:43]=2)[CH2:27][CH2:28]1

Participants

7

Reactant 5

HCID 7519AnisoleHCID 62657Potassium Phosphate, TribasicHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 6484228Thiomorpholine 1,1-dioxideHCID 66605177HCID 66605177, compound

Product 1

HCID 66605478HCID 66605478, compoundYield 72.8%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

A microwave vial containing a mixture of biphenyl-2-yldicyclohexylphosphine (13 mg, 0.037 mmol), thiomorpholine 1,1 dioxide (30 mg, 0.22 mmol), methyl 7-chloro-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (88 mg, 0.186 mmol), potassium phosphate, tribasic (59 mg, 0.28 mmol), and tris(dibenzylideneacetone)dipalladium(0) (8.5 mg, 9.3 μmol) was flushed with nitrogen. DME (0.4 mL) was added and the vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine and the product was captured on an SCX column, washed with EtOAc and MeOH and then removed with 2N NH3 in MeOH and DCM. The solvent was removed and the crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (74 mg). This was dissolved in TFA (5 mL), anisole (0.142 mL, 1.30 mmol) was added, and the reaction was heated at 75° C. for 4 hr. Solvents were removed and the product was captured on an SCX column, washed with MeOH, and released with 2N NH3 in MeOH to leave crude methyl 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (61 mg). It was suspended in 7 N NH3 in MeOH (7 mL) and heated at 85° C. for 17 hr in a sealed microwave vial. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=100:0 to A:B=40:60 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-(1,1-dioxido-4-thiomorpholinyl)-2-(6-methyl-3-pyridinyl)-5H-pyrido[3,2-b]indole-4-carboxamide (14 mg, 0.031 mmol, 23% yield) as a yellow solid. MS (ESI) m/z 436.10 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1H, br. s.), 9.31 (1H, d, J=2.01 Hz), 8.54 (1H, s), 8.49(1H, dd, J=8.18, 2.39 Hz), 8.35 (1H, s), 8.10 (1H, d, J=8.81 Hz), 7.87 (1H, s), 7.41 (1H, d, J=8.31 Hz), 7.31 (1H, d, J=2.27 Hz), 7.07 (1H, dd, J=8.81, 2.01 Hz), 3.87 (4H, d, J=4.78 Hz), 3.22 (4H, d, J=4.03 Hz), 2.55 (3H, s).

Workup

  1. additionA microwave vial containing
  2. customwas flushed with nitrogen
  3. additionDME (0.4 mL) was added
  4. customthe vial was sealed
  5. customThe reaction was partitioned between EtOAc and water
  6. washThe organic phase was washed with brine
  7. washwashed with EtOAc and MeOH
  8. customremoved with 2N NH3 in MeOH and DCM
  9. customThe solvent was removed
  10. dissolutionThis was dissolved in TFA (5 mL)
  11. temperaturethe reaction was heated at 75° C. for 4 hr
  12. customSolvents were removed
  13. washwashed with MeOH

Sources & evidence

ORD record
ord-09dc70b62c454638ba2292d7d9a9ebff
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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